1999 Albert Lasker Award

Roderick MacKinnon

LABORATORY OF MOLECULAR NEUROBIOLOGY AND BIOPHYSICS

Many of the body’s processes, from conscious, coordinated movements like walking to automatic ones like a regular heartbeat, rely upon a carefully calibrated system of chemical and electrical communication along cellular pathways. In 1890, German chemist Wilhelm Ostwald theorized that bioelectric signals might be initiated by ions — electrically charged atoms — passing into and out of cells. But one particular question — how these electrical messengers manage to penetrate the normally impermeable cell membrane — occupied biochemistry laboratories for an entire century, until 1998, when Rockefeller University’s Roderick MacKinnon zeroed in on the answer by revealing the structure and mechanism of the cell’s most ubiquitous gateway: the potassium ion channel. For his discoveries, Dr. MacKinnon received the 1999 Albert Lasker Basic Medical Research Award.

Twentieth-century research revealed much about the mechanisms of cell signaling, and by the 1950s, it had been established that ions gain access inside the cell via narrow channels in the cell membrane, each of which opens selectively for a particular ion — sodium, potassium, calcium or chloride — and that these channels act as conduits for all electrical signaling in the body; an ion passing through its assigned channel triggers an electrical signal that is sent from cell to cell to cell. The next question — exactly how the molecular machinery of an ion channel works — would require another half-century to break open.

Numerous scientists tried for decades to employ x-ray crystallography to catch a structural glimpse of an ion channel. But the difficulty of isolating integral membrane proteins — of which ion channels are composed — renders them particularly elusive to structural examination. Because bacterial membrane proteins are easier to work with than those of plants or animals, Dr. MacKinnon used ion channels from the bacterium Streptomyces lividans, and so doing was the first person to achieve a high-resolution structure of an ion channel: the potassium channel, present in almost all biological cell types and central to a large variety of cellular activities.

Dr. MacKinnon’s assembled picture not only gave the world its first glimpse of the channel’s structure, but also showed how ion channels open and close. He discovered sensors situated at the outer edge of each ion channel that are coded to respond to particular signals in order to open or close a molecular “gate.” The sensors of so-called “calcium-activated” channels, for example, respond to an increase in the concentration of calcium ions. Ligand-gated channels react when a signaling molecule such as a neurotransmitter binds to a receptor on the cell surface. Sensors for voltage-gated channels — which Dr. MacKinnon modeled in later research — pick up on electric voltage over the cell membrane.

Dr. MacKinnon’s atomic-level picture also helped resolve the conundrum over ion selectivity in potassium channels. For decades, researchers wondered how the potassium ion channel blocks sodium ions, which are smaller than potassium ions, from entrance. Dr. MacKinnon showed that the membrane proteins that make up the potassium channel are aligned in such a way that their electrically negative oxygen atoms point toward the passage. The chemistry of the selectivity filter at the entrance to the potassium channel induces potassium ions to shed the four water molecules with which they travel and bind instead to those oxygen atoms, a trade that maintains the ion’s electrical charge. The smaller sodium ion cannot reach all of the pore’s oxygen atoms and therefore cannot leave behind its water molecules. The selectivity filter, which is water-averse, blocks it from passing.

Dr. MacKinnon’s work opened up entirely new avenues of research in biochemistry and biology. In addition to making muscle movements possible, potassium ions generate electrical activity that creates power for the heart and brain; control the muscle that lines the arteries, helping to regulate blood pressure; and are instrumental in the secretion of metabolic hormones like insulin. Dr. MacKinnon’s discoveries, therefore, also offered fresh insight into a wide variety of disorders that are caused by abnormalities in ion channel function, including epilepsy, ataxia, migraine, heart arrhythmia and cystic fibrosis, among many others. Dr. MacKinnon shared the 1999 Lasker Award with Clay Armstrong of the University of Pennsylvania School of Medicine and Bertil Hille — a Rockefeller University alumnus — of the University of Washington School of Medicine.

CAREER

Dr. MacKinnon received his B.A. in biochemistry from Brandeis University and his M.D. from Tufts University School of Medicine. He completed his medical residency at Beth Israel Hospital, Harvard Medical School, and postdoctoral work at Brandeis. He joined the faculty at Harvard Medical School before moving to Rockefeller in 1996. Dr. MacKinnon is a member of the National Academy of Sciences. In addition to the Lasker Award, he is the recipient of the 2003 Nobel Prize in Chemistry, the 2003 Louisa Gross Horwitz Prize, the 2001 Gairdner Foundation International Award, the 2001 Perl-UNC Neuroscience Prize and the 2000 Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science.

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